Fungicidal compositions



United States Patent 3,224,935 FUNGllCIDAL COMPOSITIONS William E. Burt, Royal Oak, Mich., assignor to Ethyl Corporation, New York, N.Y., a corporation of Virginia N0 Drawing. Filed Dec. 22, 1961, Ser. No. 161,387 6 Claims. (Cl. 167-30) This invention relates to fungicidal compositions, and more particularly, to fungicidally potent organometallic compounds and their use in combating fungi.

An object of this invention is to provide new fungicidal compositions. Still another object is to provide a new means for combating fungi. A further object is to provide new fungicidal compositions comprising conditioning agents and certain organometallic compounds as described herein.

The above and other objects are accomplished by the present invention which resides in providing fungicidal compositions comprising a conditioning agent and as a principal active ingredient, a compound having the formula where M is a metal of Group IVB of the Periodic Table, X is a halogen and R and R are selected from the class consisting of hydrogen and hydrocarbon radicals having one to four carbon atoms. Hence, R and R may be methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, and the like. Compounds of this type can be prepared by reacting the met-a1 tetrahalide with the appropriate sodium cyclopentadienide according to the general method of Wilkinson et a=l., J. Am. Chem. Soc, 76; 4281 (1954).

X in the above formula represents a halogen atom. The fungicidally active compounds of this invention are either fluorine, chlorine, bromine or iodine derivatives of the Group IVB metals. The most preferred halogen is chlorine. For example, the compound bis(cyclopentadienyl) titanium dichloride, which exhibits high fungicidal activity, is a chloro derivative of the Group IVB metal, titanium.

M in the above formula is an atom of the Group IVB metals titanium, zirconium, and hafnium. Because the compounds of titanium and zirconium are more stable than the corresponding hafnium compounds, the metals, titanium and zirconium, are preferred. Generally, the most stable compounds are the titanium derivatives, and for this reason, titanium compounds of the type represented by the above formula are the most preferred compounds. However, some of the zirconium derivatives such as bis(cyclopentadienyl) zirconium dichloride, exhibit high fungicidal activity, and these zirconium derivatives are highly preferred also.

The cyclopentadienyl radicals in the above formula can be either alike or different. In other words, the compounds may be either symmetrical or unsymmetrical. The compounds are symmetrical when R is equal to R and similarly, they are unsymmetrical when R, is different from R A symmetrical compound is illustrated by bis(methylcyclopentadienyl) titanium dichloride and an unsymmetrical compound is represented by cyclopentadienyl methylcyclopentadienyl zirconium dichloride. Because the symmetrical compounds are more easily prepared, this class of compounds is preferred. Hence, the compounds bis(cyclopentadienyl) titanium dichloride, bis(methylcyclopentadienyl) titanium dichloride, bis(isopropyl cyclopentadienyl) zirconium dichloride, bis(tertbutyl cyclopentadienyl) titanium dichloride, and the like,

are preferred.

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The most preferred compounds are bis(cyclopentadienyl) titanium dichloride and bis(cyclopentadienyl zirconium dichloride. These compounds have high fungicidal activity.

Such compounds as described above are useful in combating fungi when they are applied to the locus of the fungi. Such treatment, therefore, constitutes one aspect of the invention. It has been found that the above materials are useful in controlling and eliminating fungi which infest vegetables, animals and man. A facet of this invention is a novel method of combating and controlling fungi. Accordingly, one embodiment of this invention is the method of combating fungi which comprises contacting the fungus with a fungitoxic amount of a compound having the formula given above. Another aspect of this invention is the provision of a method for controlling fungi which comprises treating matter susceptible to fungal infestation with the compound of the above formula.

For maximum effectiveness, the active ingredient of the present invention is admixed in fungicidally effective amount with a conditioning agent of the type commonly referred to as a pest controlled adjuvant or modifier. Such adjuvants have been referred to by names such as conditioning agent, dispersing agent, surface active agent, and surface active dispersing agent. Their purpose is to extend the active ingredient to assure its eflicacious penetration of, or application to, the locus being treated and to adapt the active ingredients for ready and eflicient application by using conventional equipment.

An advantage of using these conditioning agents is that the fungicidally active compounds may be too effective or too potent when used alone to be of practical utility. Another advantage derived from the use of these adjuvants is to permit field application by methods readily employed and still obtain effectively complete coverage of the material being protected.

Formulations of the fungicidally active ingredient with a suitable conditioning agent comprise both liquid and solid types as Well as the aerosol type of formulation. The liquid type of formulation can have Water, an organic solvent, or an oil-water emulsion and the like as the conditioning agent.

It is also intended that the term conditioning agent include solid carriers such as talc, attaclay, kieseguhr, chalk, diatomaceous earth, and the like, and various mineral powders, such as calcium carbonate, which act as a dispersant, as a carrier, and in some instances, perform the function of a surface active agent.

The conditioning agent may also be an industrial commodity such as paint, raw polymer, finished plastic and the like. Such industrial materials act as a diluent, dispersant, Wetting agent, and extender for the active in gredient, thus, enhancing its fungicidal action.

The formulations of this invention, therefore, cornprise the above defined fungicidally active ingredient in a suitable material as a disperant or conditioning agent. It is not intended that this invention be limited to any specific proportions of active ingredient and condition ing agent. The important feature of the invention is to provide a formulation of such concentration that is appropriate for the desired application. The conditioning agent will be present to provide the proper type of contact with the material being protected.

Nor is it intended that the invention be limited to the use of a fungicidally active ingredient in the presence of only a compound or product or material known as a conditioning agent. It has been found that other additives are useful in the preparation of the fungicidal preparations. Other materials found useful are classified as spreading agents and adhesives. Spreading agents tend to increase the area covered by a spray liquid.

Many chemicals act as both wetting and spreading agents. Dried blood (blood albumin), sulfite lye, both in the liquid and dehydrated forms, and petroleum emulsions belong to this group. Adhesives increase the adherence of the active agent to the treated surface to augment resistance to wear and mechanical action. Bentonite and other clays, gelatin and glue, are examples of adhesives.

As mentioned previously, the fungical preparations are in the form of either liquid or dry or aerosol formulations. Liquid compositions, either solutions or dispersions, frequently also contain a surface active dispersing agent in amounts sufficient to render the composition readily useful in aqueous spray application. The surface active dispersing agents referred to herein are sometimes known as wetting, dispersing or penetrating agents. They are agents which cause the formulations to be easily dispersed in water. They can be of the anionic, cationic, or nonionic type and include salts of long chain fatty acids, sulfonated oils, both vegetable and animal, petroleum oils, sulfates of long chain alcohols, phosphates of long chain alcohols, various polyethylene oxides, condensation products of ethylene oxide with alcohol and phenols, quaternary ammonium salts, and the like. The surface active agent will usually be present to the extent of 0.1 to 5 percent of the formulation. Typical of the liquid formulations is the water solution or dispersion of the active ingredients. Example I below, is an example for the preparation of an aqueous suspension of a typical active ingredient described in this invention.

The active ingredients can also be dispersed or suspended in various organic solvents such as alcohols, ketones, hydrocarbons, and petroleum fractions such as kerosene, dimethylformamide, and the like. In these cases a surface active dispersing agent is usually present to provide ready dispersability with water.

The solubility of the active ingredients of this invention in organic solvents, furthermore, is such that they can be applied advantageously in the form of a solution in this type of solvent. In certain uses, this type of vehicle is preferred, for example, in treating cloth, leather, or other fibrous articles. In these applications, it is preferred to apply the pesticides dissolved in a volatile solvent. After application, the volatile solvent evaporates leaving the fungicide impregnated throughout the surface of the article and in the dispersed form which has been found to be most advantageous. Likewise, in applying the fungicides to smooth surfaces, as for example in treating wood, a solution may be the most practical vehicle for applying the protective film. Brushing, spraying, or dipping may be the application method of choice. The choice of an appropriate solvent is deter mined largely by the solubility of the active ingredients which it is desired to employ, by the volatility required in the solvent, by the spreading or flow characteristics thereof, and by the nature of the material being treated. Typical formulation of this type is described in Example II below.

Another typical formulation of the fungicidal ingredients is an oil in water emulsion (see Example III). Generally these are prepared by dissolving the fungicidally active ingredient in an organic solvent, usually a petroleum fraction like kerosene, and then dispersing this solution with vigorous agitation in a large volume of water containing a minor amount of a surface active agent.

In addition to the adjuvants and other ingredients described above, it has been found that one can incorporate an adherant or sticking agent such as vegetable oils, naturally occurring gums, and other adhesives in the active ingredient formulations. Likewise, humectants can be employed in the formulations. Furthermore, the formulations can be employed in admixture with other pesticidal materials or other biocides such as insecticides,

d larvacides, bactericides, germicides, miticides or with other materials which it is desired to apply along with the fungicides. In like manner, two or more of the active ingredients may be formulated together in a single composition, thus achieving control of a broader spectrum of fungi.

Fungicides can be applied in dry media as well as in liquid suspensions or solutions. In fact, early practice in the art used dust formulations almost exclusively. It was only the advent of the introduction of spray machinery that caused dust formulations to be considered with disfavor. However, it was soon realized that spraying was often not as convenient as dusting, particularly when large, comparatively inaccessible cultivated fields are to be treated or when the area of interest necessarily requires that it be treated with a dry agent. Dust formulations of my active compounds have a ready place in the art and indeed the use of these dry formulations should grow with time, since they are utilizable when treating large areas for fungicidal infestation by airplane dusting. Dusting is also extensively employed in treating man and animals for fungicidal infestations.

A measure of the utility of the dust formulation is the impressive amount of research which has been performed in this area. The particles shape, the size, density and hardness, and the nature of the dry diluent have been shown to be factors which are important as well as the absorption and absorption characteristics thereof. Therefore, another desired and efficacious formulation of the fungicidally active ingredient is a dust formulation which is prepared generally by milling the active ingredient in ball mill within the presence of a dry material, for example, fullers earth. After milling, the mixture is screened and the fraction passing through a very fine sieve is collected. Thereafter, a further dilution is made by repeating the above procedure with an additional very large amount of a compound such as fullers earth. Evample IV exemplifies a dust formulation. A preferred formulation of the compounds comprises a wettable powder. In preparing wettable powders, several formulation procedures are possible (see Example V for one type of procedure). It is one intention of this invention to provide compositions comprising the active ingredient defined herein in combination with a minor amount of surface active agent. Such surface active agents can be chosen for example from those previously mentioned in connection with aqueous dispersion. Still other surface active agents can be employed, the above merely showing a representative list of the more common material. Such formulations can be readily admixed with a solid carrier. Formulations thus formed then comprise the active ingredient of this invention, an inert carrier, and a surface active agent. Among the inert carriers which can be employed in preparing wettable powders are soya bean flour, tobacco flour, walnut shell flour, gypsum, mica, talc, apatite, pumice and the like. In preparing concentrated wettable powders it is preferred to employ between 0.01 and 5 percent of the surface active agent, based upon the amount of active ingredient, and up to percent of the inert carrier based upon the total amount of the formulation. Such concentrated formulations provide the advantage of permitting economical storage and transportation of the fungicide and permit further dilution by simple admixture with water at the time of application.

The compounds described above are also active in colloidal formulations. A colloidal formulation is prepared by passing a mixture of the active ingredient, a hydrocarbon solvent and a large amount of water through a colloid mill until homogenation of the oil and water is achieved. Example VI gives an example of the preparation of a colloidal formulation.

The compounds also find effective use when formulated in aerosol formulations, i.e., when mixed with a liquid of low boling point that changes to a gas when released from a confined space. Exampies of diluent used in these formulation are fluorinated hydrocarbons such as tetrafiuoromethane, and hexafluoroethane. Mixed halogenated compounds containing fluorine and chlorine such as difiuorodichloromethane and pentafiuorochloroethane and the like can also be used as the liquid having the necessary low boiling point. Other materials such as carbon dioxide, sulfur dioxide, hydrogen sulfide and ammonia can be used, and of these, carbon dioxide generally is preferred. One method of preparing such aerosol formulations comprises introducing my new compounds into a pressure cylinder and later introducing the liquifying diluent under pressure followed by mixing the cylinder to obtain uniform solution. If desired, smaller containers can then be filled from the cylinder in which the formulation is prepared. In many cases it is desirable to add a second solvent to the low boiling material of the type described above so as to more readily dissolve my compounds. Examples of such cosolvents are benzene, acetone, carbon tetrachloride and the like. Example VII is an example of the preparation of an aerosol type formulation of my active ingredient.

My compounds are also effective when formulated in an ointment for topical application to the epidermis of animals and man. A typical ointment formulation is given in Example VIII below.

It is not intended that the finished formulations of my fungicidally active compounds be limited to any particular concentration range. The concentration range desired in my invention is that range necessary to accomplish the desired end. A preferred range for agricultural application is between 0.1 and 2,000 parts per million. Formulations containing as high as 30 percent active ingredient are used in treating animals and man. Typical formulations of this invention are described in the following examples in which all parts are by weight.

The compounds in the following examples will have the designations given below:

EXAMPLE I (WATER SUSPENSION) A formulation of Compound I is prepared by adding, with vigorous agitation, parts of this material to 1,000 parts of water containing 1 part of Tween-80. This concentration dispersion is further diluted 1,000 times by the addition of water to obtain a formulation of suitable concentration for application. Thus, the resulting dispersion contains 10 parts per million of my fungicide in the water dispersion.

EXAMPLE II (ORGANIC SOLUTION) A solution consisting of 5 parts of Compound II in 250 parts of cyclohexanone is prepared by stirring the two constituents for a period of two minutes at a temperature of about 25 C. This concentrated solution suitable for storage or transportation is further diluted with 99,750 parts of kerosene to form a final dilution of 50 p.p.m. suitable for application.

EXAMPLE III (OIL IN WATER EMULSION) An oil and water emulsion is prepared by dissolving 10 parts of Compound III in 1,000 parts of kerosene. This solution is dispersed with vigorous agitation in 99,000 parts of water containing one part of Triton X100 to provide a dispersion containing 100 ppm. of active ingredient.

6 EXAMPLE IV (DUST FORMULATION) A dust formulation of the fungicide is prepared by adding one part of Compound IV to parts of fullers earth in a ball mill. The mixture is milled for a period of one hour, screened to collect a fraction passing a 100 mesh sieve. This one percent formulation can be applied directly or further diluted. Further dilution is made by repeating the above procedure with an additional 9,900 parts of fullers earth.

EXAMPLE V (WETTABLE POWDER) A mixture of 100 parts of Compound V, 1,000 parts of attaclay and 0.01 part of Nacconol is intimately mixed in an L-shaped blender. The 10 percent wettable powder thus prepared produces a satisfactory water suspension when 11 parts are stirred into 10,000 parts of water, producing a suspension containing 100 ppm. active in gredient.

EXAMPLE VI (COLLOIDAL FORMULATION) A colloidal formulation is prepared by passing a mixture of 10 parts of Compound VI, 100 parts of kerosene, 1000 parts of water and 1 part of mannitan monooleate through the colloid mill until homogena'tion of the oil in water is achieved.

EXAMPLE VII (AEROSOL FORMULATION) Into a cylinder rated at 100 p.s.i. working pressure, is introduced 10 parts of Compound VII. The cylinder is then made pressure tight except for one opening through which is introduced a mixture of 10 parts acetone and 50 parts of dischloro difiuoromethane from a container at 2000 p.s.i. The cylinder into which the ingredients are introduced is then sealed off and inverted to give a uniform aerosol solution of my active materials in the mixture of co-solvents.

EXAMPLE VIII (OINTMENT) 2000 parts of Compound VIII is ground in a ball mill until it is no longer gritty and then passed through a fine mesh sieve. The powder is then transferred to a suitable mixing vessel and 10,000 parts of white petrolatum, U.S.P., is added. The mixture is mixed until all powder is suspended within the petrolatum in the form of a fine paste. Then the remainder of 998,000 parts of white petrolatum it added and the mixture again thoroughly mixed until a homogenous product is obtained.

The fungicidal effectiveness of my compounds was demonstrated by one or more of the following tests.

A gar-Plate Technique The compounds were screened for anti-fungial activity by the Agar-Plate Technique against five fungi representing groups of economic importance. The test fungi and their occurrences are as follows:

Aspergillus niger-Mildew of fabrics and leather, molding of fruit, bakery goods and stored grain.

Penicillium expansum-molding of stored grain, hay and fruit.

Alternaria solani-Early blight of potato and tomato.

Glomerella cingulnta-Bitter rot of apples.

Trychophyton interdigitale-Pathogenic for man and animals.

Specifically, the method was the Agar-Plate Technique, USDA Circular No. 198, pages 12 and 14, 1931. The medium employed was Sabouraud Dextrose Agar. This medium is used for carrying the stock cultures as well as for the test itself. The agar is put into solution and then cooled to 4245 C. To this is added a saline spore suspension of the test organism. The inoculated agar is then poured into sterile Petri dishes and allowed to harden. A suitable amount of the compound tested was placed on a one square centimeter area in the center of the agar. If the compound was solid, the compound was sprinkled upon this area of the plate. When the compound was a liquid, a depression was cut out in the center of the agar by means of a cork borer having a diameter of 1.5 mm. Four drops of the liquid compound were placed in this depression. The agar plates were incubated for days at 25 C. If the compound is inhibitory, a zone of clear agar will be noted around the area of inoculation. The size of this zone is measured, and is an indication of the inhibitory value of the compound tested. The diffusability of the compound will affect the area of inhibition. If the compound tested has no antifungicidal activity, there will be no area of inhibition, and in some cases, growth will appear under the compound tested.

Serial dilution tests The sample was tested for activity against the same five fungi utilized in the Agar Plate Technique. The fungi for all tests were grown in a Bacto Sabouraud liquid medium, pH of 5.7. The sample was dissolved in a minimal quantity of ethanol and diluted with sterile water thereafter to give an original concentration of 512 p.p.m. The test cultures were grown upon the Bacto Sabouraud Dextrose Agar for days. A heavy spore suspension was prepared in buffered distilled water. The inoculum for each tube was one drop of the heavy spore suspension. The test cultures werei ncubated at 30 C. for 10 days. An effective concentration of 250 parts per million (p.p.m.) is generally accepted as the maximum concentration at which a chemical can be considered for use as an agricultural fungicide.

Further screening of representative types of these compounds was carried out by the serial dilution test according to Burlingame and Reddish, J. Lab. Clin. Med. 24, page 765, 1939. The test fungi used in this case were Trichophyton interdigitale, Triclzophyton rubrum, T rycophyton schoenleinii, Microsporum audouini, Epidermaphyton floccosum, Microsporum gypseum. These fungi were grown in Difcos Sabourauds liquid medium, pH 4.7. Sample preparation consisted of dissolving aliquots of each compound in 10 mls. of ethanol and diluting to 512 p.p.m. concentrations with distilled Water. These stock solutions were serially diluted through 10 tubes of culture medium. The inoculum consisted of 1 dropper tube of a heavy spore suspension of the test fungi. The tests were incubated at 35 C. for one week.

Particular effectiveness of the samples in this series of tests indicates possible therapeutic use in the treatment of athletes foot, ringworm of the nails and scalp and external fungal infection of animals. Some presently commercial fungicides, utilized in this field of therapy, contain an active ingredient in concentrations as high as 30 percent by Weight (300,000 parts per 1,000,000).

Foliar fungicide screening Cereal Leaf Rust Wheat is grown in soil in paper pots with -30 plants per pot. When the plants are 6-8 inches tall, they are sprayed with the test solutions (300 p.p.m. and 75 p.p.m. concentration), with three pots used for each treatment applied. After the spray treatments have dried thoroughly, the plants are sprayed with a suspension of spores of wheat leaf rust disease, Puccinia rubigovera, reared on live Wheat leaf culture. After one Week to ten days, disease symptoms are observed and percent control obtained by comparison of the sample with inoculated controls and manzate-treated positive controls.

Tomato late blight.Susceptible species tomato plants are treated from seed and transplanted into soil in individual paper pots. When they are 6 to 8 inches high, they are sprayed with the test solutions (300 p.p.m. and 75 ppm. concentration) with three plants used for each treatment applied. After the spray treatments have dried thoroughly, the plants are sprayed with a suspension of spores of the tomato late blight fungus, Phytopht/zora infestans, which is reared on lima bean agar Cir culture. After a few days to one week disease symptoms are observed and percent control obtained by comparison of the sample with inoculated controls and manzate-treated positive controls.

Powdery mildew 0f cucumbers.Susceptible species cucumbers are grown in soil in paper pots with 23 plants per pot. When the first leaf has reached a size of about 3 inches in diameter, they are sprayed with the test solutions (300 p.p.m. and p.p.m. concentration) with 3 pots used for each treatment applied. After the spray treatments have dried thoroughly, the plants are dusted with spores of powdery mildew fungus, Erysiphe cichoraceurum, reared on live cucumber leaf culture. After one week to ten days, disease symptoms are observed and percent control obtained by comparison of the sample with inoculated controls and Karathane-treated positive controls.

Agar plate [Zone 01 inhibition in millimeters] *See footnote below.

Serial dilution [Minimum effective concentration in p.p.m. 250 p.p.m. or less considered good activity] An Pc As Gc Ti* Bis(cyclopentadienyl) zirconium di- *An=Asper r;z'llus nil er; Pe=Peniclllium arpamum; As=Allemuria solanl; Gc= (Zlomerella cingttlatu; Ti= Trycophylun interdigitale.

I claim: 1. A fungicidal composition consisting of (a) as a principal active ingredient a compound having the formula wherein M is selected from the class consisting of titanium and zirconium and R is selected from the class consisting of hydrogen and the methyl and butyl radicals,

(b) from 0.1 to 5 weight percent of a surface active dispersing agent as a dispersant therefor, and

(c) the remainder of said composition consisting essentially of a solid carrier selected from the class consisting of talc, attaclay, kieselguhr, chalk, diatomaceous earth, soybean flour, tobacco flour, walnut shell flour, gypsum, mica, apatite, pumice and fullers earth.

2. A fungicidal composition of claim 1 wherein said principal active ingredient is bis(cyclopentadienyl) zirconium dichloride.

3. A fungicidal composition of claim 1 wherein said principal active ingredient is bisQcyclopentadienyl) titanium dichloride.

4. Method of combating fungi comprising treating the locus of the fungi with a fungitoxic amount of a compound having the formula wherein M is selected from the class consisting of titanium and zirconium and R is selected from the class 9 consisting of hydrogen and the methyl and butyl radicals.

5. Method of combating fungi comprising treating the locus of the fungi with a fungitoxic amount of b.is(cyclopentadienyl) zirconium dichloride.

6. Method of combating fungi comprising treating the locus of the fungi with a fungitoxic amount of bis(cyclopentadienyl) titanium dichloride.

References Cited by the Examiner UNITED STATES PATENTS 2,178,099 10/1939 Gornitz et a1 260431 2,208,253 7/1942 Flenner et al. 16722 2,278,965 4/1942 Van Peski et al. 260-429 2,818,416 12/1957 Brown et a1 '260429 2,818,417 12/1957 Brown et al. 260-429 2,839,552 6/1958 Shapiro et al. 260-429 2,864,843 12/1958 De Witt et al. 260429 2,898,354 8/1959 Shapiro et a1. 260-429 2,916,503 12/1959 Kozikowski 260429 2,964,547 12/1960 De Witt et a1. 260-429 Brown et al. 260-429 Gash 260--242 Shapiro et al. 260--429 De Witt et al. 260429 Weinmvayer 260439 Graham 260439 Closson et a1 260429 Sandel 23-14 Thomas 260438 Haslam 260429.5

Haven 260439 OTHER REFERENCES Encyclopedia of Chemical Technology, entries: Carbonyl Compounds, Carbonyl, vol. 3, pp. 201-205, published 1949 by Interscience Encyclopedia, Inc.,

LEWIS GOTTS, Primary Examiner.

M. O. WOLK, Examiner. 

1. A FUNGICIDAL COMPOSITION CONSISTING OF (A) AS A PRINCIPAL ACTIVE INGREDIENT A COMPOUND HAVING THE FORMULA 